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The Long-term Natural History of the Weekly Symptomatic Status of Bipolar I Disorder
Lewis L. Judd, MD;
Hagop S. Akiskal, MD;
Pamela J. Schettler, PhD;
Jean Endicott, PhD;
Jack Maser, PhD;
David A. Solomon, MD;
Andrew C. Leon, PhD;
John A. Rice, PhD;
Martin B. Keller, MD
Arch Gen Psychiatry. 2002;59:530-537.
ABSTRACT
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Background To our knowledge, this is the first prospective natural history study
of weekly symptomatic status of patients with bipolar I disorder (BP-I) during
long-term follow-up.
Methods Analyses are based on ongoing prospective follow-up of 146 patients
with Research Diagnostic Criteria BP-I, who entered the National Institute
of Mental Health (Bethesda, Md) Collaborative Depression Study from 1978 through
1981. Weekly affective symptom status ratings were analyzed by polarity and
severity, ranging from asymptomatic, to subthreshold levels, to full-blown
major depression and mania. Percentages of follow-up weeks at each level as
well as number of shifts in symptom status and polarity during the entire
follow-up period were examined. Finally, 2 new measures of chronicity were
evaluated in relation to previously identified predictors of chronicity for
BP-I.
Results Patients with BP-I were symptomatically ill 47.3% of weeks throughout
a mean of 12.8 years of follow-up. Depressive symptoms (31.9% of total follow-up
weeks) predominated over manic/hypomanic symptoms (8.9% of weeks) or cycling/mixed
symptoms (5.9% of weeks). Subsyndromal, minor depressive, and hypomanic symptoms
combined were nearly 3 times more frequent than syndromal-level major depressive
and manic symptoms (29.9% vs 11.2% of weeks, respectively). Patients with
BP-I changed symptom status an average of 6 times per year and polarity more
than 3 times per year. Longer intake episodes and those with depression-only
or cycling polarity predicted greater chronicity during long-term follow-up,
as did comorbid drug-use disorder.
Conclusions The longitudinal weekly symptomatic course of BP-I is chronic. Overall,
the symptomatic structure is primarily depressive rather than manic, and subsyndromal
and minor affective symptoms predominate. Symptom severity levels fluctuate,
often within the same patient over time. Bipolar I disorder is expressed as
a dimensional illness featuring the full range (spectrum) of affective symptom
severity and polarity.
INTRODUCTION
KRAEPELIN1 HAD described manic-depressive
insanity as a cyclical illness. Until recently, following his lead, clinical
and research attention concerning mood disorders was concentrated on the most
severe syndromal manifestations of these disorders, ie, manic and major depressive
episodes (MDE).2-9
However, recent evidence suggests that the concept of bipolar I disorder (BP-I)
with episode-free periods of euthymia punctuated by syndromal MDE and mania
is inadequate.10-12
Analyses of weekly symptomatic status during the long-term course of another
mood disorder, unipolar MDD,12 has shown that,
although this illness has traditionally been examined primarily in terms of
the onset, remission, and relapse of MDEs, minor and subsyndromal depressive
symptoms dominate its long-term course by nearly a 3:1 ratio (43% vs 15% of
follow-up weeks). Patients with unipolar MDD were found to be symptomatic
during 60% of the follow-up period and to experience a changeable course in
which major, minor, and subsyndromal depressive symptoms alternated within
the same patient over time. In brief, unipolar MDD is expressed longitudinally
as a dimensional illness involving the full spectrum of depressive symptom
severity.
This new understanding of the long-term symptomatic structure of unipolarity
stimulated us to carry out a similar analysis of the longitudinal symptom
structure of BP-I, based on weekly levels of symptom severity and polarity
in a large cohort of patients with BP-I who entered the National Institute
of Mental Health (Bethesda, Md) Collaborative Depression Study (CDS)13-14 during a major affective episode.
We hypothesized that BP-I would also be expressed longitudinally as a dimensional
illness in which patients typically experience frequent changes in polarity
and severity of affective symptoms covering the full range of severity of
depression and mania.
We also examined 2 new potentially useful measures of chronicity in
relation to predictors of chronicity previously identified for BP-I, as follows:
(1) the total percentage of follow-up weeks that patients experienced the
full-syndromal level of major depressive or manic symptoms and (2) the total
percentage of follow-up weeks they experienced any
affective symptoms at any level of severity. We anticipated greater chronicity
for BP-I than we previously found for unipolar MDD, and we predicted that
our 2 new indices, characterizing chronicity during the entire follow-up period,
would provide a somewhat different but complementary picture than previously
reported for BP-I.
SUBJECTS AND METHODS
SUBJECTS
The analysis sample consisted of 146 patients with BP-I entering the
CDS from 1978 through 1981 at 1 of 5 academic centers during an affective
episode.13-14 Patients experienced
both depressive and manic episodes as of intake or during follow-up, with
no evidence of schizophrenia or schizoaffective disorder. Bipolar I diagnosis
was based on the Schedule of Affective Disorders and Schizophrenia15 using Research Diagnostic Criteria (RDC).16 Subjects were white (genetic hypotheses were being
tested), spoke English, had an IQ score of at least 70, and had no evidence
of organic mental disorder or terminal medical illness. All patients gave
informed consent at the 5 academic sites where the data were gathered. Demographic
and clinical characteristics are presented in Table 1.
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Table 1. Demographic and Clinical History Characteristics of Patients
With Bipolar I Disorder at CDS Intake*
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FOLLOW-UP PROCEDURES
Trained raters interviewed patients every 6 months for the first 5 years
of follow-up and are still continuing to interview them yearly thereafter,
using variations of the Longitudinal Interval Follow-up Evaluation (LIFE).17 Patient interviews were the primary information source
for LIFE data, with chronological memory prompts used to obtain information
on changes in weekly symptom severity for all mood and other mental disorders.
Interviews were supplemented by detailed review of available medical records
and all information was integrated into a final rating algorithm score. Weekly
symptom ratings were obtained using LIFE Psychiatric Status Rating (PSR) scales,
which are anchored to diagnostic thresholds for RDC mental disorders. Collaborative
Depression Study raters routinely undergo rigorous training, resulting in
high intraclass correlation coefficients (ICCs) for rating changes in symptoms
(ICC = 0.92), recovery from episodes (ICC = 0.95), and subsequent reappearance
of symptoms (ICC = 0.88).
Interviewers assign a 5-point rating of the accuracy of weekly PSR information
based on their overall impression of the subject's recall, the internal consistency
of information provided, and evidence of denial or distortion of illness status.
If a subject is severely manic or depressed at the scheduled time of follow-up,
the interview is rescheduled at a later time. Of the 2516 forms available
for the analysis sample, 25.8% were rated "excellent," 50.4% "good," 20.7%
"fair," 2.7% "poor," and 0.4% "very poor" in their accuracy of weekly PSR
information. Specific follow-up weeks were not included in the analyses if
accuracy ratings were "poor" or "very poor" (9.0% of follow-up weeks accounting
for 77 forms) or if there were missing data (0.9% of weeks). Due to frequent
changes in symptom status, it was inappropriate to impute illness status during
a period of inaccurate or missing data.
A total of 157 CDS patients met diagnostic criteria for BP-I and were
followed up for up to 20 years. Because our study focused on the long-term
course, we eliminated from the analyses 11 patients (7.0%) with less than
2 years of weekly PSR data with "fair" or better accuracy. Nine of these patients
dropped out before 2 years; the remaining 2 excluded subjects were followed
up for exactly 2 years but had missing data or forms with "poor" or "very
poor" accuracy for some portion of that time. This left 146 patients with
BP-I with at least 2 years of weekly follow-up data rated "fair" or better
accuracy.
CLASSIFICATION OF WEEKLY SYMPTOM SEVERITY LEVELS
We have extended the methodology used in our previous work, describing
the course of unipolar MDD,12 to include symptom
severity levels of mania as well as depression. Each weekly symptom severity
level was assigned as presented in Table
2, based on the 6-point PSR scale for major depression and mania
plus the 3-point PSR scale for rating minor depression/dysthymia, hypomania, DSM-IV atypical depression, DSM-III
adjustment disorder with depressed mood, and RDC cyclothymic personality.
While affective symptom severity levels are anchored to the diagnostic thresholds
for all depressive and manic conditions, including MDE, minor depressive/dysthymic
disorder, mania, and hypomania, weekly levels were assigned regardless of
whether the patient was in an RDC-defined episode. Affective symptoms below
the thresholds of the foregoing RDC conditions were classified as subsyndromal
depression or subsyndromal mania. Weeks with no affective symptoms were classified
as asymptomatic. Weeks with some affective symptoms were then categorized
into levels of pure depression (no mania/hypomania), pure mania/hypomania
(no depression), or a combination of manic and depressive symptoms (cycling/mixed
affect). Weeks with prominent psychotic symptoms were counted based on a PSR
score of 6 on the 6-point PSR scale for mania or MDE.
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Table 2. Classification of Affective Symptom Severity Levels Based
on Weekly PSR Scale Scores Across All 4 Groups of Affective Disorders*
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STATISTICAL ANALYSES
Follow-up weeks spent in the different symptom status categories were
computed for each patient as percentages of the total number of follow-up
weeks with PSR ratings of "fair" or better accuracy. Total and average yearly
numbers of changes in symptom status categories and shifts in symptom polarity
were also computed per patient. Subgroups of patients with BP-I were defined
based on predictors of chronicity previously identified in the BP-I literature:
age; age at onset of first lifetime affective episode; number of lifetime
affective episodes; poor social functioning in the 5 years prior to intake;
family history of affective disorder; alcoholism; and duration, polarity,
and presence of psychotic features in the intake episode. Although not previously
identified as robust predictors of chronicity in BP-I, we also examined sex,
severity of the intake episode, drug-use disorder, and comorbid anxiety disorders.
We defined long-term chronicity in 2 ways: (1) the total percentage of follow-up
weeks spent with symptoms at the full-syndromal MDD/manic level, and (2) the
total percentage of follow-up weeks spent with any affective symptoms (at
any level other than the asymptomatic status). Comparisons were made by analyses
of variance, with a 2-tailed  level of .05 defining statistically significant
group comparisons.
RESULTS
SYMPTOM STATUS DURING THE COURSE OF ILLNESS
Patients were symptomatically ill about half of the time (mean [SD],
47.3% [34%]; median, 38%) and asymptomatic for the remainder of follow-up
(52.7% [34%]; median, 62%). Fourteen patients (9.6%) of 146 were symptomatic
during all of their prospective follow-up (a finding not attributable to these
patients having a shorter follow-up period). Symptomatically ill weeks (47.3%
of follow-up) included a mean ([SD]; median) of 14.8% ([18.7%]; median, 7.5%)
of all follow-up weeks with subsyndromal symptoms of mania or depression;
20.2% ([21.0%]; median, 12%) of total follow-up with minor depression/dysthymia
or hypomanic symptoms, and only 12.3% ([14.2%]; median, 7%) of follow-up spent
at the syndromal threshold level of mania and/or MDE. Notably, the 5 CDS centers
did not differ in the percentage of weeks patients with BP-I spent with some
affective symptoms or asymptomatic (F4,141 = 1.06; P = .38).
As presented in Table 3,
patients experienced 3 times more depressive symptoms (31.9% of total follow-up
weeks) than manic symptoms (9.3% of weeks), and depressive symptoms were 5
times more frequent than cycling/mixed symptoms (5.9% of weeks). Subsyndromal
and minor depressive/dysthymic symptoms were much more prevalent than MDE-level
symptoms (22.9% vs 8.9% of weeks); subsyndromal manic and hypomanic symptoms
were 3 times more common than symptoms at the threshold for mania (7.0% vs
2.3% of weeks). Overall, most of all symptomatic weeks involved subsyndromal,
minor depressive, and hypomanic symptoms (74.0%). Only 12.3% of all follow-up
weeks were spent with symptoms at the threshold for MDE or mania. During RDC-defined
MDEs, patients with BP-I had symptoms at the full symptomatic threshold for
only 32.6% of weeks; during RDC-defined manic episodes, they experienced the
full manic symptom threshold for only 20.5% of weeks.
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Table 3. Percentage of Follow-up Weeks Spent at Specific Affective
Symptom Categories Defined by Symptom Polarity and Severity During Long-term
Follow-up of 146 Patients With Bipolar I Disorder in the CDS*
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PERCENTAGE OF WEEKS WITH PSYCHOTIC SYMPTOMS
Patients with BP-I spent 2.3% of total follow-up weeks with psychotic
symptoms—1.3% of weeks occurred during mania and 0.9% weeks during MDE.
Throughout their entire course, approximately half of patients (47.3%) had
some weeks with psychotic symptoms—26.0% had psychotic symptoms during
MDEs and 28.1% during manic episodes.
CHANGES IN SYMPTOM STATUS
A change in symptom status was defined as any week-to-week change in
symptom severity level and/or polarity. As presented in Table 4, patients experienced a mean (SD) of 74.3 (115.1) changes
in symptom status during the entire follow-up, or 5.9 (7.6) times per year.
Only 9.6% patients averaged 1 or fewer changes in affective symptom status
per year. More than half of the sample (54.1%) changed affective symptom status
more than 3 times per year, 34.9% more than 5 times per year, 11.6% more than
10 times per year, and 5.5% more than 20 times per year.
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Table 4. Affective Symptom Severity Characteristics During Long-term
Follow-up of 146 Patients With Bipolar I Disorder in the CDS*
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CHANGES IN AFFECTIVE SYMPTOM POLARITY
A substantial portion of the symptom status changes involved shifts
in symptom polarity, that is, between some level of depression and some level
of mania/hypomania. This occurred a mean (SD) of 47.2 (110.8) times during
extended follow-up, or 3.5 (7.4) times per year. About 60% of patients changed
polarity once per year or less, while 19.2% changed polarity an average of
more than 5 times per year, 8.2% changed polarity more than 10 times per year,
and 4.1% changed polarity more than 20 times per year.
PATIENT COMBINATIONS OF SYMPTOM STATUS CATEGORIES
Overall, 90% of patients spent 1 or more weeks during follow-up with
depressive symptoms and 86.3% had 1 or more weeks with manic/hypomanic symptoms.
Only approximately half (48.6%) had 1 or more weeks with cycling/mixed affective
symptoms (Table 4). In addition,
35 patients (24.0%) spent 1 or more weeks during follow-up in all 7 possible
symptom categories (ie, 3 levels of depressive symptom severity, 3 levels
of manic/hypomanic severity, and the asymptomatic status). Another 41 patients
(28.1%), during their course of illness, experienced 6 of the 7 symptom categories
(and of these patients, 10% had no weeks asymptomatic); 27 (18.5%) spent 1
or more weeks at 5 symptom categories, 29 (19.9%) at 4 categories, 11 (7.5%)
at 3 categories, and only 8 (2.1%) in 2 symptom categories. Of the 132 patients
with 1 or more weeks symptomatic in the depressive spectrum, 105 (79.5%) experienced
all 3 levels of depressive severity. Of the 126 patients with manic symptoms,
61 (48.4%) experienced all 3 levels of the manic symptom spectrum.
PREDICTORS OF CHRONICITY DURING FOLLOW-UP
Greater chronicity, defined in terms of a significantly higher percentage
of follow-up weeks with symptoms at the full-syndromal MDE/mania level, as
well as weeks with any level of affective symptom
severity, was significantly associated with 4 predictors: poor social functioning
in the 5 years prior to intake, a longer total duration of the intake episode,
depressive-only or cycling/mixed (vs manic-only) polarity of the intake episode,
and having an RDC diagnosis of drug-use disorder as of intake or during follow-up.
Sex, age at intake, age of onset of first affective episode, total number
of affective episodes, history of affective disorder in first-degree relatives,
severity of intake episode, psychotic features of the intake episode, and
RDC diagnosis of alcoholism were not significantly associated with increased
chronicity (Table 5). Research
Diagnostic Criteria–diagnosed anxiety disorders (generalized anxiety
disorder, panic disorder, phobic disorder, and obsessive-compulsive disorder),
considered individually as well as in the aggregate, also did not predict
an overall more chronic course.
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Table 5. Percentage of Follow-up Weeks Spent With Symptoms at the Disorder
Threshold for MDD/Mania or Any Level of Affective Symptom Severity During
Long-term Follow-up of 146 Patients With Bipolar I Disorder in the CDS by
Various Predictors of Chronicity*
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COMMENT
Previous reports3-9,18
on the long-term picture of BP-I have largely focused on the course of MDE
and manic episodes or have examined it from the perspective of patterns of
successive epochs of illness, such as the "kindling" model.18-20
These epoch-based analyses of major affective episodes have informed us about
this illness. However, we had a different objective: to document the long-term
symptomatic structure of this disorder based on summary (aggregate) measures
of weekly affective symptom status. To the best of our knowledge, this is
the first article describing the entire long-term weekly naturalistic course
of BP-I in terms of the full range of affective symptoms.
We believe that the measures examined here provide a more complete picture
of the longitudinal structure of BP-I, which complements past approaches focusing
only on major depressive/manic episodes, and provide valuable new information
about the long-term course of this illness.
While BP-I is less chronic than unipolar MDD, which did not support
our a priori hypotheses of increased chronicity of BP-I, these patients were
nonetheless symptomatically ill nearly half of their long-term follow-up.
Although BP-I is traditionally described in terms of episodes of MDE and mania,
we found that subthreshold, minor depressive/dysthymic, and hypomanic symptoms
were the modal expressions of BP-I during its prospective course. Symptoms
in the depressive spectrum predominated substantially over manic (3:1) or
cycling/mixed symptoms (5:1). We cannot, however, rule out the possibility
that patients with more distressing depressive symptoms may be more likely
to enter and remain in a long-term prospective study. Bipolar I is often regarded
as a psychotic disorder, yet slightly more than half of the patients had no
weeks with psychotic symptoms during the entire course of illness; psychotic
symptoms occurred relatively more frequently during manic than MDD episodes.
Patients experienced frequent changes in symptom status and polarity in a
dynamically fluctuating course. The full range of subsyndromal, minor depressive/dysthymic,
hypomanic, MDE, and manic symptoms were observed commonly within the same
patients over time. In sum, these data strongly support the idea that the
longitudinal course of BP-I is expressed as a dimensional spectrum involving
the complete range of severity of depressive and manic symptoms. We therefore
submit that longitudinal descriptions of the BP-I course that do not include
all levels of affective symptom severity and polarity are incomplete.
The definitions of chronicity we have used in this article, namely,
the percentage of all follow-up weeks spent at the highest level of affective
symptom severity or with any affective symptoms, are new but provide a complementary
perspective of the long-term course of BP-I. Other analyses of chronicity
in BP-I have used a variety of definitions based on specific epochs of time,4-8
such as time to recovery from the intake episode, time to first prospectively
observed MDE or manic episode relapse, relapse to MDE/manic episode(s) within
a specified period of time, occurrence of an MDE/manic episode during a particular
follow-up interval,5 or level of morbidity
during a particular period. Only Turvey et al8
analyzed predictors of the overall percentage of follow-up spent in major
affective episodes. However, their analyses, as all other studies of the long-term
course of BP-I, focused only on MDE and manic episodes rather than the more
frequent periods of minor depression, dysthymia, or hypomania. To the best
of our knowledge, our study is the first to characterize all of long-term follow-up based on the full range of syndromal and
subsyndromal levels of affective symptom severity. Our approach presents a
definitive picture of the overall chronic nature of BP-I compared with other
definitions based only on selected follow-up intervals, which have produced
inconsistent findings. We also found that 2 indices of past chronicity, namely,
poor social functioning in the 5 years prior to intake and a longer intake
episode, predicted significantly greater symptomatic chronicity during all
of follow-up. To earlier findings that cycling in the intake episode predicted
greater chronicity,4, 7 we now
add that a purely depressive intake episode also predicts greater chronicity
compared with purely manic intake episodes. Unlike Coryell et al,5 who found that alcoholism predicted chronicity, defined
as being in an MDE or manic episode during the 15 years of follow-up, we found
that drug abuse but not alcoholism predicted greater chronicity of both MDE
and manic symptoms, and these affective symptoms remain during long-term follow-up.
Inconsistent findings in chronicity underscores the need for reliable and
meaningful definitions of chronicity, such as the ones we have proposed.
Generalization to other samples of BP-I may be limited because the CDS
cohort consisted of severely ill, tertiary care, white patients. We do not
know the extent to which the history and intake status of our sample are representative
of other patients with BP-I seeking treatment. Although interrater agreement
for changes in episode status has been shown to be high, there may be some
degree of error in assigning weekly symptom severity levels. We may have underestimated
the time with subsyndromal symptoms and overestimated the asymptomatic time
since PSR coding rules do not allow for subsyndromal symptoms to be coded
following fully asymptomatic episode recovery until such time as symptoms
again reach syndromal levels. Cycling/mixed expressions may have been relatively
uncommon because a universally accepted definition of these forms did not
exist when the Schedule of Affective Disorders and Schizophrenia instrument
was developed in the late 1970s; thus, our analyses cannot shed light on the
question of dysphoric mixed states using contemporary definitions. Nonetheless,
the CDS is a unique database for the perspective symptomatic study of the
long-term symptomatic structure of BP-I. Now that the Zurich Study2, 21 has closed, the CDS is the only available,
ongoing prospective naturalistic follow-up study of a large cohort of patients
with affective disorder of which we are aware.
Algorithms to summarize the dose intensity of mood stabilizers, antidepressants,
and antipsychotic medications have been created and updated over the years
to reflect new treatments that have become available since the study began
in 1978.22 However, the CDS is a naturalistic
follow-up study of mood disorders, not a controlled treatment investigation.
Meaningful analyses of the adequacy, intensity, and effect of antidepressant,
antimanic, and antipsychotic medications on the various levels of affective
symptom severity would be extremely complex and are beyond the scope of this
article. The predominance of depressive over manic/hypomanic symptoms should
not be interpreted as suggesting the need for more aggressive use of antidepressant
medications in the absence of a mood stabilizer since there is some evidence
that antidepressants may induce mania or cycle acceleration in some bipolar
patients.23
Analyses of within-subject trends over time for particular subgroups
of interest, such as patients with BP-I with various patterns of cycling or
comorbid substance abuse, are also beyond the scope of our study. The focus
of this article is on characterizing in the aggregate the overall long-term
symptomatic status of BP-I based on the sample as a whole. The relatively
large variation around the means of the long-term outcome measures we have
presented suggests that these indices may be useful for identifying and characterizing
clinically meaningful subgroups of patients with BP-I, which we intend to
address in future manuscripts.
While these data support the idea that bipolar disorder is best characterized
as a spectrum of affective symptom severity,24
they do not imply a continuum between BP-I and BP-II, which may have rather
distinct course patterns.25-26
Nor can we comment on contemporary imaginative proposals to extend the bipolar
spectrum to "softer" expressions, such as pharmacologic hypomania, cyclothymic,
and impulse-control disorders.27-29
Our data more properly pertain to a dimensional continuum of bipolar symptom
severity from subsyndromal to full-blown syndromal levels within the course of rigorously defined BP-I. Kraeplin,1
who wondered why manic-depressive episodes erupted periodically, had suggested
that someday the origin of the illness would be understood from relatively
inconspicuous subsymptomatic foundations that persist between episodes. These
data provide support for his conceptualization.
AUTHOR INFORMATION
Submitted for publication December 12, 2000; final revision received
August 6, 2001; accepted September 4, 2001.
Funds for the conduct of this study were provided in part by the Roehr
Fund of the University of California, San Diego.
This manuscript has been reviewed by the Publications Committee of the
Collaborative Depression Study and has its endorsement.
From the National Institute of Mental Health Collaborative Program on
the Psychobiology of Depression, Clinical Studies, conducted with the participation
of the following investigators: M. B. Keller, MD (Chairperson, Providence,
RI); W. Coryell, MD (Co-Chairperson, Iowa City, Iowa); H. S. Akiskal, MD,
L. L. Judd, MD, J. D. Maser, PhD (San Diego, Calif); P.W. Lavori, PhD, T.
I. Mueller, MD, M. T. Shea, PhD (Providence); J. Fawcett, MD, W.A. Scheftner,
MD (Chicago, Ill); W. Coryell, MD, J. Haley (Iowa City); J. Endicott, PhD,
A. C. Leon, PhD, J. Loth, MSW (New York, NY); J. Rice, PhD, T. Reich, MD (St
Louis, Mo). Other contributors include: N. C. Andreasen, MD, PhD, P. J. Clayton,
MD, J. Croughan, MD, G. L. Klerman, MD , R. M. A., Hirschfeld, MD,
M. M. Katz, PhD, E. Robins, MD, R.W. Shapiro, MD, R. L. Spitzer, MD, G. Winokur,
MD, and M. A. Young, PhD.
Deceased.
Corresponding author and reprints: Lewis L. Judd, MD, Department
of Psychiatry at the UCSD Department of Psychiatry, 9500 Gilman Dr, La Jolla,
CA 92093-0603.
From the Departments of Psychiatry, University of California–San
Diego, (Drs Judd, Akiskal, Schettler, and Maser); Department of Research and
Training, Columbia University, New York, NY (Dr Endicott); and Department
of Psychiatry, Brown University, Providence, RI (Drs Solomon and Keller),
Cornell University, Ithaca, NY (Dr Leon), and Washington University, St Louis,
Mo (Dr Rice).
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